Process Validation for Drug Product
AGENDA • Policies and practices • Examples of good practices • Discussion and clarification www.gmpsop.com 2
POLICIES • Scope • Production Processes used for producing a Drug Product or In- Process Material for a drug product • Existing, new and modified processes • Includes the filling of the product into the primary package where the filling process may impact the critical quality attributes of the drug product • Filling of tablets and capsules is defined in Packaging Validation www.gmpsop.com 3
POLICIES • Responsibility • The Site Validation Team is accountable for ensuring that process validation is executed according to the guidelines • Prepare Validation Requirements and Documentation www.gmpsop.com 4
POLICIES • Prospective validation • Use for substantially modified or new processes • Complete validation before any batches release • Concurrent validation • For orphan drugs, infrequently manufactured products, legacy processes without changes and minor changes to validated processes • One batch released at a time • Retrospective • Legacy processes without changes • Historical look back, no batch release involved www.gmpsop.com 5
POLICIES • To Use Concurrent or Retrospective • Well understood and documented process • Critical process parameters and quality attributes identified and used • Sufficient data available generated using Validated or Pharmacopoeia Test Methods • In-process controls and acceptance criteria established • No significant product/process failures attributable to causes other than operator error or equipment failure • Impurity profiles established for the API www.gmpsop.com 6
POLICIES • Retrospective Data Sources • Lot records • Process control charts • Maintenance log books • Change control records • Process performance (e.g., capability studies) • Finished product data including trend and stability results • Examine 10-30 consecutive and most recent lots for consistency, include failures www.gmpsop.com 7
POLICIES • Critical Process Parameters & Quality Attributes • Define and justify • A parameter is critical if it can affect a Critical Quality Attribute • A process step containing a critical parameter is critical • Normal Operating Ranges in protocol must have supporting data (e.g., Tech Transfer Package, historical site data) • Must be within Proven Acceptable Range and Regulatory Range • Use risk assessment to determine critical parameters for validation • If supporting data is not applicable to commercial scale, establish and reference in validation report www.gmpsop.com 8
Figure 1 – Process Parameters Lower Normal Operating Upper Normal Operating Normal Operating Range Lower Regulatory Upper Regulatory Regulatory Range Upper PAR Lower PAR Proven Acceptable Range Lower Edge-of-Failure Upper Edge-of-Failure Low Parameter High www.gmpsop.com 9
POLICIES • Critical Process Parameters • Include Environmental Controls if applicable • Include Microbiological Quality if applicable www.gmpsop.com 10
CASE STUDY: POWDER ORAL SUSPENSION (POS) TRANSFER FROM DEVELOPMENT TO VALIDATION • Critical process parameters are often defined during development and qualified during validation • Milling was defined as a critical processing step • Formulation is predominantly sucrose and particle size reduction is required for the final POS presentation • Issue: no acceptance criteria (“report value”) for screens testing of mill samples • Resolution: • Comparison of screens data both before and after milling serves to qualify milling parameters • Comparison of biobatch data to validation lot data showed similarity and therefore, consistency of process www.gmpsop.com 11
POLICIES • Validation lot size • Same as commercial • Small scale can be used • Scale changes can be concurrently validated • Number of validation lots • At least 3, consecutive • Must be run within approved ranges • All must meet protocol acceptance criteria • Manufactured to manufacturing instructions defined in protocol www.gmpsop.com 12
POLICIES • Master Manufacturing Instructions • Must be developed prior to the protocol being written • Must be approved prior to validation execution • Master Production Order is based on this • Validation protocol • critical steps, critical process parameters, sampling requirements and acceptance criteria • approved by the validation team before validation activity begins www.gmpsop.com 13
POLICIES • Changes to approved protocols • Issue new revision or supplemental documentation • Document justification of change • Approvals as original protocol, attach to original • Document in report • Changes in parameters • Critical assessed as to impact on validation • Non critical documented and justified • All must be within regulatory www.gmpsop.com 14
CASE STUDY: DEVIATION HANDLING • Progressive levels of documenting quality anomalies (any or all of the following may be required): Validation Deviation Worksheet • Protocol specific • • Evaluates the need for corrective action • Corrective Action Worksheet Requires applicable department mgmt sign-off • Includes due date • Validation Test Result Out Of Acceptance Criteria Form • • Created as a result of a recent 483 • Must be completed without exception Requires Quality review and sign-off • Laboratory Investigation Report • Applies to all routine and validation results that are outside of acceptance • criteria • Quality Assurance Report – Investigation Documents all manufacturing deviations • Documents conclusions regarding lot release • www.gmpsop.com 15
POLICIES • Validation test conditions • Standard production conditions • Challenge/extremes documented in development and/or Quality • Hold times (includes storage times) • Documented evaluation • Consider using batches for stability www.gmpsop.com 16
POLICIES • Homogeneity (J, .9) • Where identified as a critical quality attribute • Physical and chemical homogeneity as applicable • Sample at discreet critical steps (e.g., mixing, freeze drying) • Representative samples • Account for start-up , interruptions, final units www.gmpsop.com 17
PROCESS CAPABILITY • During initial process validation, process capabilities were calculated for dosage uniformity of a new tablet product: • 20 mg (n=250 cores) – 2.40 • 40 mg (n=380 cores) – 2.35 • 80 mg (n=330 cores) – 2.41 • “Good” process capability is defined as between 1.34 and 3.00 www.gmpsop.com 18
PROCESS CAPABILITY (CONT’D.) 40 MG UNIFORMITY Potency 0491K99 0493K99 0949K02 45 0950K02 44 0951K02 43 Target 42 QAAL LL mg/core 41 QAAL UL 40 SpecR LL * 39 SpecR UL * 38 Avg-2 std dev 37 Avg+2 std dev 36 Avg-3 std dev 35 Avg+3 std dev 1 2 7 8 13 14 19 20 LL LR SC Shift 1 Shift 2 Sample ID Avg= 40.0 Std Dev= 0.72 www.gmpsop.com 19
PROCESS CAPABILITY (CONT’D.) 40 MG CPK ANALYSIS Uniformity 140 Target 120 -2sp Mean +2sp 100 LSL USL -3sp +3sp 80 60 40 20 0 34 36 38 40 42 44 46 Samples: 380 Cpk: 2.35 Min, Max: ( 37.5, 42.4) Mean: 39.9908 3sp Lim: ( 37.441, 42.541) Std Dev: .84992 Spec Lim: ( 34, 46) Target: 40 Est % out: ( .0000, .0000) www.gmpsop.com 20
POLICIES • Bracketing & Matrixing • Used for multiple strengths, lot sizes, process parameters, and equipment items • Minimum 3 lots worst case • Documented rationale for approach and justification of worst case • Be careful, may need to review with Regulatory Agency • Consistency must be demonstrated for all batches • Entire study must be written as a single final report www.gmpsop.com 21
CASE STUDY: MQ PROCESS VALIDATION Group Filling Target Protein Solid % Total Solution Filling concentration concentration Solids Strengths volume (mg/ml) (mg/ml) (mg) (ml) 1 0.2 0.1 2.2 16.7 1.7 1 0.4 0.1 4.4 18.9 1.9 2 0.6 0.15 4.4 14.3 1.4 2 0.8 0.15 5.9 15.5 1.6 2 1.0 0.15 7.3 17.0 1.7 2 1.2 0.15 8.8 18.5 1.8 3 1.4 0.3 5.1 10.0 1.0 3 1.6 0.3 5.8 10.7 1.1 3 1.8 0.3 6.6 11.4 1.2 3 2.0 0.3 7.3 12.2 1.2 www.gmpsop.com 22
CASE STUDY: MQ PROCESS VALIDATION Group Strength Bulk Size FD Capacity No. of (mg) (kg) (magazines) Batches 1 0.2 7-7-7 42-84-84 3 1 0.4 7 84 1 2 0.6 22 420 1 2 0.8 7 42 1 2 1.0 7 42 1 2 1.2 7-13-22 42-210-420 3 3 1.4 8-22-40 42-210-420 3 3 1.6 8 42 1 3 1.8 8 42 1 www.gmpsop.com 23 3 2.0 22 210 1
POLICIES • Raw Materials and components • purchased, stored and approved according to approved procedure • Changes in API for multiple strength products must include one lot at high dose and low dose • Changes in API supplier (previously Policy Memo) • Chemical and physical evaluation of three lots of API with comparison to multiple lots of old API • Drug product validation for multiple strengths must include one lot at high dose and low dose • For multiple dosage forms, include one lot of each dosage form www.gmpsop.com 24
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